Spironolactone aqueous compositions

ABSTRACT

Disclosed herein is a stable, ready-to-use liquid formulation comprising spironolactone and its method of use.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 17/111,578, filed on Dec. 4, 2020, which is a continuation ofU.S. patent application Ser. No. 16/878,092, filed on May 19, 2020, nowU.S. Pat. No. 10,888,570, which is a continuation of U.S. patentapplication Ser. No. 16/823,604, filed on Mar. 19, 2020, now U.S. Pat.No. 10,660,907, which is a continuation of U.S. patent application Ser.No. 16/682,477, filed on Nov. 13, 2019, now U.S. Pat. No. 10,624,906,which is a continuation of U.S. patent application Ser. No. 15/665,014,filed on Jul. 31, 2017, now U.S. Pat. No. 10,493,083, which is acontinuation-in-part of U.S. patent application Ser. No. 15/337,559,filed on Oct. 28, 2016, now U.S. Pat. No. 9,757,394, which claimspriority to U.S. Provisional Patent Application No. 62/495,583, filed onOct. 30, 2015.

FIELD OF THE INVENTION

Spironolactone aqueous compositions are described herein, as well as amethod of manufacture and of use thereof.

BACKGROUND OF THE INVENTION

Spironolactone (CAS Registry No. 52-01-7) is commercially available astablets (e.g., ALDACTONE®). Spironolactone is an aldosterone antagonisthaving utility as a potassium sparing diuretic. (ALDACTONE®(spironolactone) Tablet Prescribing Information, as of Oct. 22, 2014.)Spironolactone is used to diagnose or treat conditions in which a personhas elevated levels of aldosterone. Aldosterone is a hormone produced bythe adrenal glands to help regulate the salt and water balance in thebody. Spironolactone is employed in the management of primaryhyperaldosteronism and the treatment of congestive heart failure.Spironolactone is also indicated for the treatment of a variety of skindisorders such as acne, hirsutism, androgenic alopecia, and rosacea.Spironolactone may also be used to treat cirrhosis of the liver,nephrotic syndrome, and essential hypertension. Spironolactone, whenadded to a standard therapy for adults with severe heart failure, hasbeen shown to result in a 30% reduction in mortality. (M. L. Buck, TheAnnals of Pharmacotherapy (2005) 39(5): 823-828.) Additionally,spironolactone has become a standard part of combination diureticregimens in infants with chronic lung disease and children with heartdisease. (M. L. Buck, The Annals of Pharmacotherapy (2005) 39(5):823-828.) Oftentimes tablet administration is not possible, especiallyfor the above-mentioned adult patients with severe heart failure or withthe pediatric patients.

As there is presently no commercial available aqueous-basedspironolactone drug product, a physician, in the clinical setting, mustrely on the pharmacy to prepare a compounded spironolactone formulation.The pharmacist, in turn, typically prepares the compoundedspironolactone formulation from the commercially available tablet orfrom powder spironolactone. Compounded formulations may be problematicfor pharmacists because of the potential for microbial contamination.Compounded formulations may be problematic for the physician, andimportantly, the patient, due to the potential errors associated withcompounding. Further, the stability of the compounded formulations isoftentimes unknown. As related to spironolactone, the literatureincludes reports by others that examine the stability of spironolactonein compounded formulations.

Gupta et al., American Journal of Hospital Pharmacy (1978), 35(11):1382-1385 examines the stability of spironolactone in a compoundedspironolactone formulation comprised of a simple syrup vehiclecontaining 10% alcohol and 0.1% sodium benzoate used as a preservative.Therein, Gupta et al. reports that the compounded spironolactoneformulation having a pH of 6.2 retains 97.4% of the initialspironolactone after 160 days. Gupta et al. explains that the compoundedspironolactone formulations described therein have limited stability butcan be used by pharmacists extemporaneously on an as-needed basis. Guptaet al. mentions that the bioavailability of the compoundedspironolactone formulation was not examined.

Mathur et al., American Journal of Hospital Pharmacy (1989) 46(10):2040-2042 report that compounded spironolactone formulations wereprepared by grinding commercially available film-coated spironolactonetablets, adding Purified Water, USP to the ground material followed bytriturating that composition to form a paste, and then suspending thepaste in Cherry Syrup, NF. Mathur et al. describe the stability ofspironolactone in three compounded spironolactone formulations withtheoretical concentrations of 2.5 mg/mL, 5.0 mg/mL, and 10.0 mg/mL.Mathur et al. also describe an HPLC assay for determining thespironolactone content over a period of time. Therein, Mathur et al.examine the concentrations of spironolactone remaining for the threecompounded spironolactone formulations at various temperatures thatrange from 5° C. to 30° C. Based on the HPLC assay results, Mathur etal. state that compounded spironolactone formulations at the statedconcentrations exhibited less than 5% degradation after four weeks ofstorage. Mathur et al. also state that microbial evaluation by the USPantimicrobial preservatives effective test showed that the samplesexhibited bacterial and fungal counts well within acceptable limits.

Pramar et al., Journal of Clinical Pharmacy and Therapeutics (1992):17(4): 245-248 report the development of a stable oral liquid dosageform of spironolactone. As a part of that study, Pramar et al. mentionthat a clear and stable oral liquid dosage form of spironolactone is notavailable because the aqueous solubility of spironolactone is reportedto be only 28 μg/mL. Pramar et al. describe ten differentspironolactone-containing liquid dosage forms with spironolactonepresent at a concentration of 0.2% w/v in a vehicle comprised mainly ofpolyethylene glycol 400 (30% v/v) and mono- and polyhydric alcohols(ethanol (10% v/v), propylene glycol (10% v/v), and glycerin (10% v/v)).Pramar et al. mention that the amounts of propylene glycol andpolyethylene glycol 400 alone were too high in order to achieve aspironolactone concentration of 2 mg/mL (i.e., 0.2% w/v). For instance,Pramar et al. explains that propylene glycol, when administered in highdoses, is known to cause lactic acidosis in children. Pramar et al.identify a particular dosage form (i.e., Formulation C), as being stablebased on accelerated testing at 40° C. and a relative humidity of 75%.Interestingly, the reported dosage forms also include phosphate orcitrate buffer (50 mM) adjusted to a final pH of 4.5, in which thereported final pH is identified therein as being the pH at whichspironolactone exhibits maximum stability. Pramar et al. DrugDevelopment and Industrial Pharmacy (1991) 17(5): 747-761; Pramar et al.Journal of Pharmaceutical Sciences (1991) 80(6): 551-553. As related tothe dosage form containing citrate, Pramar et al. mention that aspironolactone-containing liquid dosage form including citrate buffer(i.e., Formulation B) is unsuitable because of the resultantinstability.

Nahata et al., The Annals of Pharmacotherapy (1993) 27(10): 1198-1199report that a compounded spironolactone formulation prepared fromtablets exhibits stability for three months. Nahata et al. criticizesthe dosage forms described in the aforementioned Pramar et al. referenceas being unsuitable for certain patients (e.g., infants) due to the highconcentrations of propylene glycol and ethanol. The compoundedspironolactone formulation of Nahata et al. containscarboxymethylcellulose as a suspending agent, “which may provide uniformdoses by minimizing settling of the drug in the bottle during use bypatients.” Despite the presence of the carboxymethylcellulose suspendingagent, Nahata et al. observe variability in concentration assaymeasurements that “was most likely attributable to sampling ofnonuniform dispersion of drug particles in the suspension.”

U.S. Pat. No. 4,837,211 to J. L. Olsen, describes aspironolactone-containing composition that purports to overcome theuniformity issue by utilizing sodium carboxymethylcellulose or a mixtureof methylcellulose and a dimethylpolysiloxane polymer. It was discoveredthat a spironolactone-containing composition comparable to thecomposition described in Example V resulted in an increase insedimentation and that uniformity could only be achieved after vigorousshaking for 60-120 seconds after storage at 25±2° C. and 40±5% relativehumidity. The extended time required to resuspend spironolactone in thecomposition is problematic in that it may result in reduced patientcompliance—especially for an elderly patient. Further, administrationerrors may arise if the spironolactone is not uniformly dispersedthroughout the composition.

Additional reports describe compounded spironolactone formulations ashaving a shelf-life stability of either 60 days (Allen et al., AmericanJournal of Health-System Pharmacy (1996) 53(19): 2304-2309) or 90 days(BasuSarkar et al. International Journal of Pharmaceutical Review andResearch (2013) 23(1): 67-70). However, these additional reports do notconsider the uniformity of the compounded suspension.

Kaukonen et al., Journal of Pharmacy and Pharmacology (1998) 50(6):611-619 recognize the drawbacks associated with the above-mentionedcompounded spironolactone formulations and the spironolactone-containingliquid dosage forms. In an effort to overcome those drawbacks Kaukonenet al. describe an oral solution of spironolactone containingwater-soluble derivatives of β-cyclodextrin (e.g., sulfobutyl etherβ-cyclodextrin (SBE7) or dimethyl-β-cyclodextrin (DM-β-CyD)). Therein,Kaukonen et al. conducted a comparative evaluation of selectedpharmacokinetic parameters of oral solutions containing spironolactoneand either SBE7 or DM-β-CyD versus a compounded spironolactoneformulation. Kaukenen et al. state that oral bioavailability of the oralsolutions is about three times greater than the compoundedspironolactone formulation. A potential drawback to the oral solutiondescribed by Kaukonen et al. is the differences in bioavailability,which would require a clinician to estimate the dosage amounts for agiven subject, and thus lead to potential dosing errors.

In view of the foregoing, there is a need for a spironolactone aqueouscomposition that is ready to use having acceptable long-term stabilityand resuspension properties that contribute to patient compliance andreduce the likelihood of dosing errors.

SUMMARY OF THE INVENTION

Disclosed herein is a stable, ready-to-use liquid formulation comprisingspironolactone and its method of use.

Also disclosed herein is a pharmaceutical composition, comprising: (a)spironolactone; (b) a xanthan gum; (c) an anti-foaming agent; (d) apreservative; (f) a dispersing agent; (g) a sweetening agent; (h) aflavoring agent; (i) optionally a buffer to maintain the pH of thepharmaceutical composition within a range described herein; and (j) asufficient amount of a water vehicle.

Further disclosed herein is a method of treating a patient having acondition, comprising administering to the patient in need thereof aliquid formulation comprising spironolactone, wherein the liquidformulation provides for a spironolactone exposure that is about 15 toabout 37% greater than a spironolactone exposure obtained when orallyadministering to a subject a tablet formulation comprisingspironolactone, and wherein the condition is one or more of heartfailure, edema, hypertension, and a skin disorder selected from thegroup consisting of acne, hirsutism, androgenic alopecia, rosacea, andcombinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the initially observed spironolactone content (% l.c.) as afunction of shake-time (in seconds) for the compositions of Example 2(grey bars) and Comparative Example 1 (black bars).

FIG. 2 shows the observed spironolactone content (% l.c.) as a functionof shake-time (in seconds) for the compositions of Example 2 (grey bar)and Comparative Example 1 (black bars) after storage at 25±2° C. and40±5% relative humidity for 3-months.

FIG. 3 shows the effect of storage at 40±2° C. and not more than 25%relative humidity on sorbate levels in amber PETE bottles (grey bars,Example 2 Composition) and white HDPE bottles (black bars, compositionsimilar to Comparative Example 1).

DEFINITIONS

The term “about” has its customary meaning, as defined in the USP,Section 8.20, which states that “about” indicates a quantity within 10%.

A stated amount for a compositional ingredient that is not preceded bythe term “about” does not mean that there is no variance for the statedterm, as one of ordinary skill would understand that there is alwayssome possibility of a degree of variability generally associated withexperimental error.

The concentration unit “% w/v” is a measure of the weight amount of aspecified ingredient based on the total volume of the composition.

As used herein, long-term storage conditions refers to storing a samplefor a designated time at 25±2° C. and 40±5% relative humidity (“RH”).For simplicity, “long-term storage conditions,” is abbreviated as“long-term storage” or “long-term.”

As used herein, accelerated storage conditions refers to storing asample for a designated time at 40±2° C. and not more than 25% RH (i.e.,≤25% RH). For simplicity, “accelerated storage conditions,” isabbreviated as “accelerated storage” or “accelerated.”

DETAILED DESCRIPTION

Disclosed herein is a pharmaceutical composition, comprising: (a)spironolactone; (b) a xanthan gum; (c) an anti-foaming agent; (d) apreservative; (e) a dispersing agent; (f) a sweetening agent; (g) aflavoring agent; (h) optionally a buffer to maintain the pH of thepharmaceutical composition within a defined range; and (i) a sufficientamount of a water vehicle.

The spironolactone may be present in an amount that ranges from 0.20%w/v to 1.0% w/v and all amounts in between, including, for example 0.3%w/v, 0.4% w/v, 0.5% w/v, 0.6% w/v, 0.7% w/v, 0.8% w/v, and 0.9% w/v. Ina particular embodiment, spironolactone is present in an amount of 0.5%w/v.

The xanthan gum may be present in an amount that ranges from 0.18% w/vto 0.36% w/v and all amounts in between, including, for example, 0.19%w/v, 0.20% w/v, 0.21% w/v, 0.22% w/v, 0.23% w/v, 0.24% w/v, 0.25% w/v,0.26% w/v, 0.27% w/v, 0.28% w/v, 0.29% w/v, 0.30% w/v, 0.31% w/v, 0.32%w/v, 0.33% w/v, 0.34% w/v, 0.35% w/v. In a particular embodiment,xanthan gum is present in an amount of 0.25% w/v.

The anti-foaming agent aids in the removal of air, such as entrappedair, from the pharmaceutical compositions described herein. Simethiconeemulsion is an example of an anti-foaming agent. The simethiconeemulsion may be present in an amount that ranges from 0.1% w/v to 0.6%w/v, and all amounts in between, including, for example, 0.2% w/v, 0.3%w/v, 0.4% w/v, 0.5% w/v. In a particular embodiment, simethiconeemulsion is present in an amount of 0.2% w/v.

The preservative aids in the preservation of the compositions describedherein against certain microbial organisms, including one or more of E.coli, P. aeruginosa, S. aureus, A. brasiliensis, B. cepacia, and C.albicans. Preservatives contemplated herein include methylparaben orpropylparaben and the salts thereof (e.g., sodium, potassium, etc.),sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene,and butylated hydroxyanisole, sorbic acid, and a sorbate salt (e.g.,sodium, potassium, ammonium, calcium, etc.) and the mixtures thereof).In a particular embodiment, the preservative is comprised of sorbic acidand a sorbate salt (e.g., sodium, potassium, ammonium, calcium, etc.).The amount of sorbic acid includes 0.025% w/v to 0.050% w/v, while theamount of sorbate salt includes 0.10% w/v to 0.20% w/v. In anotherparticular embodiment, the preservative is comprised of 0.025% w/v to0.050% w/v of sorbic acid and 0.10% w/v to 0.20% w/v of potassiumsorbate, and in yet another embodiment, the preservative is comprised of0.050% w/v of sorbic acid and 0.20% w/v of potassium sorbate. One ofordinary skill will appreciate that the equilibrium pKa-value of sorbicacid and sorbate is about 4.8. Accordingly, the molar amounts of sorbicacid and sorbate in the pharmaceutical composition described hereindepend on the pH of the composition. Therefore, one of ordinary skillwould appreciate that the amount of sorbate (i.e., sorbic acid andpotassium sorbate) in the pharmaceutical composition refers to theamount added during manufacture.

The dispersing agent aids in dispersing spironolactone in thepharmaceutical compositions described herein. Contemplated dispersingagents, include, for example, propylene glycol, glycerin, or a mixturethereof. In a particular embodiment the dispersing agent is glycerin. Inanother embodiment, the pharmaceutical composition comprises from 1.8%w/v to 2.4% w/v glycerin, and all amounts in between, including, forexample, 1.9% w/v, 2.0% w/v, 2.1% w/v, 2.2% w/v, and 2.3% w/v.Specifically contemplated amounts range from 1.9% w/v to 2.3% w/vglycerin, from 2.0% w/v to 2.2% w/v, or from 2.1% w/v to 2.2% w/vglycerin.

The sweetening agent aids in the palatability of the pharmaceuticalcompositions described herein. Contemplated sweetening agents, include,for example, sucralose, ammonium glycyrrhizinate, acesulfame-K,aspartame, saccharin, a saccharin salt (e.g., sodium, potassium,calcium, etc.), sodium cyclamate, and mixtures thereof. The amount ofsweetener can vary according to the desired sweetness and that amount ofsweetening agent depends at least in part on the amount ofspironolactone. The percentage amount of the sweetening agent containedin a pharmaceutical composition described herein ranges from 0.005% w/vto 10% w/v, from 0.05% w/v to 5% w/v, or from 0.1% to 1% (w/v). In aparticular embodiment, the sweetening agent comprises from about 0.04%w/v to 0.6% w/v (more particularly 0.14% w/v) sodium saccharin and from0.03% w/v to 0.04% w/v ammonium glycyrrhizinate, based on the content ofglycyrrhizic acid.

The flavoring agent likewise aids in the palatability of thepharmaceutical compositions described herein. Contemplated flavoringagents include, e.g., cherry, orange, banana, strawberry or otheracceptable fruit flavors, or mixtures of cherry, orange, and otheracceptable fruit flavors. The amount of flavoring agent can range, forexample, from 0.1% w/v to 0.5% w/v. In a particular embodiment, theflavoring agent comprises a banana flavor in the amount of 0.3% w/v.

The buffer, when present, serves to maintain the pH of thepharmaceutical compositions described herein within a defined range.Suitable buffers include those buffers described in, for example, G. L.Flynn, “Buffers—pH Control within Pharmaceutical Systems,” J. ParenteralDrug Assoc. (1980) 34(2): 139-162. A suitable buffer is one that is notonly capable of maintaining a pH that ranges from 4.5 to 5.5, but alsobe compatible with the pharmaceutical composition described herein.Suitable contemplated buffers included, for example, acetate, aconitate,glutarate, glutamate, malate, succinate, tartrate, citrate, andphosphate. A specifically contemplated buffer is comprised of citricacid, monobasic citrate, dibasic citrate, and tribasic citrate, in whichthe mono-, di-, or tribasic citrate forms have associated counterions,and thus, may collectively be referred to as citrate salts, or inparticular, a citrate salt. The associated counterions include, forexample, sodium, potassium, ammonium, calcium, etc. For instance, aparticular citrate salt contemplated herein is sodium citrate, which mayexist as a hydrated form, such as, a dihydrate or a pentahydrate. In aparticular embodiment, the buffer molar concentration ranges from about10 mM to about 100 mM, which corresponds to a buffer comprised of 0.07%w/v to 0.0.7% w/v citric acid and 0.18% w/v to 1.86% w/v of a citratesalt. One of ordinary skill will appreciate that the bufferconcentration can be any numerical value between about 10 mM to about100 mM, including for example, 15 mM, 20 mM, 25 mM, 30 mM, 35, mM, 45mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM and 95mM. In another embodiment, the buffer is comprised of 0.20% w/v citricacid and 0.43% w/v sodium citrate dihydrate. One of ordinary skill willunderstand that the molar amounts of citric acid and sodium citrate,relative to each other, will depend on the pH of the composition.Therefore, one of ordinary skill would appreciate that the amount ofcitrate (i.e., citric acid and sodium citrate) in the pharmaceuticalcomposition refer to the amount added during manufacture. In aparticular embodiment, the pH of the pharmaceutical composition rangesfrom about 4.5 to about 5.5, from about 4.8 to about 5.5, from about 4.8to about 5.4, from about 4.8 to about 5.3, or from about 4.8 to about5.0.

The pharmaceutical compositions described herein have an acceptableviscosity that ranges from 100 cP to 300 cP, and all amounts in between,including, for example, 110 cP, 120 cP, 130 cP, 140 cP, 150 cP, 160 cP,170 cP, 180 cP, 190 cP, 200 cP, 210 cP, 220 cP, 230 cP, 240 cP, 250 cP,260 cP, 270 cP, 280 cP, and 290 cP. In a particular embodiment, theviscosity of the pharmaceutical composition ranges from 130 cP to 170cP.

Pharmaceutical compositions described herein are stable when stored in aclosed container, as evidenced by, for example, the amount ofspironolactone being 100.0±10.0% of labeled content (“l.c.”). Data showsthat pharmaceutical compositions described herein have a spironolactonecontent that is 100±10% l.c. when stored under long-term conditions for12-months regardless whether the container is stored in an uprightposition or on its side. Data also shows that pharmaceuticalcompositions described herein have a spironolactone content that is100±10% l.c. when stored under accelerated conditions for 6-monthsregardless whether the container is stored in an upright position or onits side. It was projected that pharmaceutical compositions describedherein have a spironolactone content of 100±10% l.c. for at least24-months, and in other instances of at least for at least 36-months.The stability may also be measured by the amount of canrenone detectedafter long-term storage. For instance, pharmaceutical compositionsdescribed herein have an amount of canrenone that is: ≤2.0% after24-months, ≤1.0% after 24-months, ≤0.5% after 24-months, or ≤0.3% after24-months after long-term storage.

It is contemplated that the pharmaceutical compositions described hereinare stored in a polyethylene terephthalate (PETE) bottle. In aparticular embodiment, the PETE bottle is amber. In another embodiment,the amber PETE bottle is enclosed using a suitable closure. In yetanother embodiment, the enclosed, amber PETE bottle has a volume of 4oz. or 16 oz. Prior to dispensing the pharmaceutical composition to anamber PETE bottle, it may be desirable to purge with an inert gas, suchas, nitrogen, and evacuate said bottle under reduced pressure. It mayalso be desirable to introduce an inert gas, such as, nitrogen, into theheadspace of the bottle once it is filled with the pharmaceuticalcomposition.

It was discovered that spironolactone resuspendability is an importantconsideration for pharmaceutical compositions described herein. For adosage form containing suspended spironolactone, sedimentation can occurafter storage for a period of time and that sedimentation results in areduced level of dosage uniformity. For example, after storage for aperiod of time when the suspended spironolactone settles at the bottomof the container, the solution above the sediment contains a loweramount of spironolactone (based on the original label content) whencompared to the originally prepared dosage form. This is especiallyproblematic for compounded dosage forms typically prepared in thepharmacy. Oftentimes, it is difficult to resuspend the settled solid atthe bottom of the container once the solid settles. If settling occurs,spironolactone dosage uniformity is unknown. This may be problematicwhen administration requires pouring a certain volume of the dosage formfrom the container. In order to deliver the appropriate dosage amount,it is critical that the spironolactone be uniformly distributedthroughout the entire volume of the dosage form. Otherwise, the patientmay receive a lower (or a higher) dosage amount than what is desired.

Pharmaceutical compositions described herein exhibit satisfactory dosageuniformity and are ready to use with minimal shaking, as determined bythe resuspendability test described below. A satisfactory dosageuniformity is based on the original label content (l.c.) of thespironolactone contained within pharmaceutical compositions describedherein. In particular, a satisfactory dosage uniformity is one where theamount of spironolactone throughout the composition is about 100% l.c.(i.e., 100±10%). A satisfactory dosage uniformity is obtained withinabout 10 seconds of shaking, within about 5 to about 10 seconds ofshaking, and within about 5 seconds of shaking regardless of the storageconditions. That is, an amount of spironolactone of about 100% l.c. maybe achieved within about 10 seconds of shaking, within about 5 to about10 seconds of shaking, or within about 5 seconds of shaking.

A first embodiment is a pharmaceutical composition, comprising: (a)0.50% w/v of spironolactone; (b) from 0.18% w/v to 0.36% w/v of axanthan gum; (c) an anti-foaming agent; (d) a preservative; (e) adispersing agent; (f) a sweetening agent; (g) a flavoring agent; (h)optionally a sufficient amount of a buffer to maintain the pH of thepharmaceutical composition from 4.5 to 5.5; and (i) a sufficient amountof a water vehicle.

In a first aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of a simethiconeemulsion; the preservative (d) is comprised of sorbic acid and a sorbatesalt; the dispersing agent (e) is comprised of glycerin; and thesweetening agent (f) is comprised of a sweetener selected from the groupconsisting of a saccharin salt, a glycyrrhizinate salt, and combinationsthereof.

In a second aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of from 0.025%w/v to 0.050% w/v of sorbic acid and from 0.10% w/v to 0.20% w/v of asorbate salt; the dispersing agent (e) is comprised of (f) 1.8% w/v to2.4% w/v glycerin; and the sweetening agent (f) is comprised of asweetener selected from the group consisting of a saccharin salt, aglycyrrhizinate salt, and combinations thereof.

In a third aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of from 0.025%w/v to 0.050% w/v of sorbic acid and from 0.10% w/v to 0.20% w/v of asorbate salt; the dispersing agent (e) is comprised of from 1.8% w/v to2.4% w/v glycerin; and the sweetening agent (f) comprises a saccharin(sodium, potassium, ammonium, calcium) salt and a glycyrrhizinate salt;and wherein the pharmaceutical composition comprises the buffercomprised of citric acid and a citrate salt.

In a fourth aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of from 0.025%w/v to 0.050% w/v of sorbic acid and from 0.10% w/v to 0.20% w/v ofpotassium sorbate; the dispersing agent (e) is comprised of from 1.8%w/v to 2.4% w/v glycerin; and the sweetening agent (f) comprises sodiumsaccharin and ammonium glycyrrhizinate; and wherein the pharmaceuticalcomposition comprises the buffer comprised of citric acid and a citratesalt.

In a fifth aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of from 0.025%w/v to 0.050% w/v of sorbic acid and from 0.10% w/v to 0.20% w/v ofpotassium sorbate; the dispersing agent (e) is comprised of from 1.8%w/v to 2.4% w/v glycerin; the sweetening agent (f) comprises sodiumsaccharin and ammonium glycyrrhizinate; and wherein the pharmaceuticalcomposition comprises the buffer comprised of from 0.17% w/v to 0.24%w/v citric acid and from 0.36% w/v to 0.48% w/v of a citrate salt.

In a sixth aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of from 0.025%w/v to 0.050% w/v of sorbic acid and from 0.10% w/v to 0.20% w/v ofpotassium sorbate; the dispersing agent (e) is comprised of from 1.9%w/v to 2.3% w/v glycerin; and the sweetening agent (f) comprises 0.14%w/v sodium saccharin and from 0.03% w/v to 0.04% w/v ammoniumglycyrrhizinate; and wherein the pharmaceutical composition comprisesthe buffer comprised of from 0.17% w/v to 0.24% w/v citric acid and from0.36% w/v to 0.48% w/v of a citrate salt.

In a seventh aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of 0.050% w/v ofsorbic acid and 0.20% w/v of potassium sorbate; the dispersing agent (e)is comprised of from 2.0% w/v to 2.2% w/v glycerin; and the sweeteningagent (f) comprises 0.14% w/v sodium saccharin and from 0.03% w/v to0.04% w/v ammonium glycyrrhizinate; and wherein the pharmaceuticalcomposition comprises the buffer comprised of from 0.17% w/v to 0.24%w/v citric acid and from 0.36% w/v to 0.48% w/v of a citrate salt.

In an eighth aspect of the pharmaceutical composition of firstembodiment, the viscosity ranges from 100 cP to 300 cP. It wasdiscovered that the viscosity of pharmaceutical compositions describedherein is an important consideration. For instance, a viscosity lessthan 100 cP may be problematic with respect to the resuspendability ofthe pharmaceutical composition. Not to be bound by theory, it isbelieved that a viscosity less than 100 cP promotes sedimentation.Further, a viscosity greater than 300 cP results in a solution that istoo viscous, which may be problematic with respect to productdispensation, i.e., the solution may become too thick to dispenseeasily.

In a ninth aspect of the pharmaceutical composition of the firstembodiment, the anti-foaming agent (c) is comprised of 0.20% w/v of asimethicone emulsion; the preservative (d) is comprised of 0.050% w/v ofsorbic acid and 0.20% w/v of potassium sorbate; the dispersing agent (e)is comprised of from 2.1% w/v to 2.2% w/v glycerin; the sweetening agent(f) comprises 0.14% w/v sodium saccharin and from 0.03% w/v to 0.04% w/vammonium glycyrrhizinate; and wherein the pharmaceutical compositioncomprises the buffer comprised of 0.20% w/v citric acid and 0.43% w/vsodium citrate.

In a tenth aspect of the pharmaceutical composition of the firstembodiment, xanthan gum is present in an amount of 0.25% w/v; theanti-foaming agent (c) is comprised of 0.20% w/v of a simethiconeemulsion; the preservative (d) is comprised of 0.050% w/v of sorbic acidand 0.20% w/v of potassium sorbate; the dispersing agent (e) iscomprised of from 2.1% w/v to 2.2% w/v glycerin; the sweetening agent(f) comprises 0.14% w/v sodium saccharin and from 0.03% w/v to 0.04% w/vammonium glycyrrhizinate; and wherein the pharmaceutical compositioncomprises the buffer comprised of 0.20% w/v citric acid and 0.43% w/vsodium citrate.

In an eleventh aspect of the pharmaceutical composition of the firstembodiment, xanthan gum is present in an amount of 0.25% w/v; theanti-foaming agent (c) is comprised of 0.20% w/v of a simethiconeemulsion; the preservative (d) is comprised of 0.050% w/v of sorbic acidand 0.20% w/v of potassium sorbate; the dispersing agent (e) iscomprised of from 2.1% w/v to 2.2% w/v glycerin; the sweetening agent(f) comprises 0.14% w/v sodium saccharin and from 0.03% w/v to 0.04% w/vammonium glycyrrhizinate; and wherein the pharmaceutical compositioncomprises the buffer comprised of 0.20% w/v citric acid and 0.43% w/vsodium citrate and the viscosity of the composition ranges from 130 cPto 170 cP.

In a twelfth aspect of the pharmaceutical composition of the firstembodiment, xanthan gum is present in an amount of 0.25% w/v; theanti-foaming agent (c) is comprised of 0.20% w/v of a simethiconeemulsion; the preservative (d) is comprised of 0.050% w/v of sorbic acidand 0.20% w/v of potassium sorbate; the dispersing agent (e) iscomprised of from 2.1% w/v to 2.2% w/v glycerin; the sweetening agent(f) comprises 0.14% w/v sodium saccharin and from 0.03% w/v to 0.04% w/vammonium glycyrrhizinate; and wherein the pharmaceutical compositioncomprises the buffer comprised of 0.20% w/v citric acid and 0.43% w/vsodium citrate, and the viscosity of the composition ranges from 130 cPto 170 cP, and the pH of the pharmaceutical composition ranges fromabout 4.5 to about 5.5.

A thirteenth aspect of the pharmaceutical composition of the firstembodiment is directed to an enclosed, amber polyethylene terephthalate(PETE) bottle comprising the pharmaceutical composition of the firstembodiment.

A fourteenth aspect of the pharmaceutical composition of the firstembodiment is directed to an enclosed, amber polyethylene terephthalate(PETE) bottle comprising the pharmaceutical composition of the firstembodiment, wherein the volume of said bottle is 4 oz. (about 118 mL) or16 oz (about 473 mL).

In a fifteenth aspect of the pharmaceutical composition of the firstembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 10 seconds.

In a sixteenth aspect of the pharmaceutical composition of the firstembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 5 to about 10 seconds.

In a seventeenth aspect of the pharmaceutical composition of the firstembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 5 seconds.

A second embodiment is directed to a pharmaceutical compositioncomprising: (a) 0.50% w/v spironolactone; (b) 0.25% w/v of a xanthangum; (c) 0.20% w/v of a simethicone emulsion; (d) a preservativecomprised of 0.050% w/v of sorbic acid and 0.20% w/v of potassiumsorbate; (e) from 2.1% w/v to 2.2% w/v glycerin; (f) a sweetening agentcontaining 0.14% w/v sodium saccharin and from 0.03% w/v to 0.04% w/vammonium glycyrrhizinate; (g) 0.30% w/v of a fruit flavoring agent; (h)a buffer comprised of 0.20% w/v citric acid and 0.43% w/v sodiumcitrate; and (i) a sufficient amount of a water vehicle.

In a first aspect of the pharmaceutical composition of the secondembodiment, the pharmaceutical composition has a pH of from 4.5 to 5.5.

In a second aspect of the pharmaceutical composition of the secondembodiment, the pharmaceutical composition has a pH of from 4.8 to 5.2.

In a third aspect of the pharmaceutical composition of the secondembodiment, the pharmaceutical composition has a viscosity that rangesfrom 100 cP to 300 cP.

In a fourth aspect of the pharmaceutical composition of the secondembodiment, the pharmaceutical composition has a viscosity that rangesfrom 100 cP to 300 cP.

In a fourth aspect of the pharmaceutical composition of the secondembodiment, the pharmaceutical composition has a viscosity that rangesfrom 130 cP to 170 cP.

A fifth aspect of the pharmaceutical composition of the secondembodiment is directed to an enclosed, amber polyethylene terephthalate(PETE) bottle comprising the pharmaceutical composition of the firstembodiment.

A sixth aspect of the pharmaceutical composition of the secondembodiment is directed to an enclosed, amber polyethylene terephthalate(PETE) bottle comprising the pharmaceutical composition of the secondembodiment, wherein the volume of said bottle is 4 oz. (about 118 mL) or16 oz (about 473 mL).

In a seventh aspect of the pharmaceutical composition of the secondembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 10 seconds.

In an eight aspect of the pharmaceutical composition of the secondembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 5 to about 10 seconds.

In a ninth aspect of the pharmaceutical composition of the secondembodiment, the shake time to achieve a uniform amount (i.e., about 100%l.c.) of spironolactone occurs within about 5 seconds.

A third embodiment is directed to a process for preparing thepharmaceutical composition of the first embodiment, which comprises: (1)mixing the xanthan gum, anti-foaming agent, preservative, a portion ofthe sweetening agent, and, optionally, the buffer, in water in a firstcontainer; (2) mixing the spironolactone, the dispersing agent, and theremaining portion of the sweetening agent in a second container; (3)transferring the contents of the second container to the first containerfollowed by mixing the contents of the first container; (4) adding theflavoring agent to the contents of the first container from step (3);(5) adding water to the first container of step (3) and mixing thecontents of the first container; (6) optionally, adding a sufficientamount of buffer to the first container to maintain the pH of thecomposition from 4.8 to 5.0; and (7) dispensing the contents of thefirst container from step (5) or the contents of the first containerinto an amber polyethylene terephthalate bottle.

A first aspect of the third embodiment is directed to a pharmaceuticalproduct prepared by the process of the third embodiment.

A second aspect of the third embodiment is directed to a pharmaceuticalproduct prepared by any one of the exemplified embodiments describedherein.

According to the above-mentioned ALDACTONE® (spironolactone) TabletPrescribing Information, ALDACTONE® (spironolactone) is indicated: (i)in the management of primary hyperaldosteronism; (ii) in the short-termpreoperative treatment of patients with primary hyperaldosteronism;(iii) in the long-term maintenance therapy for patients with discretealdosterone-producing adrenal adenomas who are judged to be pooroperative risks or who decline surgery; and (iv) in the long-termmaintenance therapy for patients with bilateral micro or macronodularadrenal hyperplasia (idiopathic hyperaldosteronism).

ALDACTONE® (spironolactone) is also indicated for edematous conditionsfor patients with congestive heart failure, for the management of edemaand sodium retention when the patient is only partially responsive to,or is intolerant of, other therapeutic measures. ALDACTONE® is furtherindicated for patients with congestive heart failure taking digitaliswhen other therapies are considered inappropriate.

ALDACTONE® (spironolactone) is also indicated for the treatment ofhypertension, to lower blood pressure; for the treatment of patientswith hypokalemia when other measures are considered inappropriate orinadequate. ALDACTONE® is also indicated for the prophylaxis ofhypokalemia in patients taking digitalis when other measures areconsidered inadequate or inappropriate.

ALDACTONE® (spironolactone) is also indicated for the treatment ofsevere heart failure (NYHA class III-IV), so as to increase survival,and to reduce the need for hospitalization for heart failure when usedin addition to standard therapy.

One of ordinary skill would understand that the pharmaceuticalcompositions described herein are useful for the indications associatedwith the ALDACTONE® drug product. One of ordinary skill would also beable to consult the ALDACTONE® prescribing information or rely on soundjudgment so as to ascertain a therapeutically effective amount of thepharmaceutical compositions described herein.

A fourth embodiment is directed to a method for the treatment of apatient in need thereof in a manner consistent with any one of theapproved indications associated with ALDACTONE®, which comprisesadministering to the subject a therapeutically effective amount of thepharmaceutical composition of the first or second embodiment.

A fifth embodiment is directed to a method for the treatment ofhypertension in a subject in need thereof, which comprises administeringto the subject a therapeutically effective amount of the pharmaceuticalcomposition of the first or second embodiment.

In a first aspect of the fifth embodiment, the composition isadministered orally or by a nasogastric tube.

A sixth embodiment is directed to a method for the treatment of severeheart failure in a subject in need thereof, which comprisesadministering to the subject a therapeutically effective amount of thepharmaceutical composition of the first or second embodiment; whereinthe composition is administered orally or by a nasogastric tube.

A seventh embodiment is directed to a method for the treatment of apatient suffering from a skin disorder, which comprises administering tothe subject a therapeutically effective amount of the pharmaceuticalcomposition of the first or second embodiment, wherein said skindisorder is selected from the group consisting of acne, hirsutism,androgenic alopecia, rosacea, and combinations thereof.

An eighth embodiment is directed to a method of treating a patienthaving a condition, comprising administering to the patient in needthereof a liquid formulation comprising spironolactone, wherein theliquid formulation provides for a spironolactone exposure that is about15 to about 37% greater than a spironolactone drug exposure obtainedwhen orally administering to a subject a tablet formulation comprisingspironolactone, and wherein the condition is one or more of heartfailure, edema, hypertension, and a skin disorder selected from thegroup consisting of acne, hirsutism, androgenic alopecia, rosacea, andcombinations thereof.

In a first aspect of the eighth embodiment, the liquid formulationcomprises spironolactone at a concentration of 5 mg/mL.

In a second aspect of the eighth embodiment, the liquid formulationcomprises 25 mg spironolactone and the tablet formulation comprises 25mg spironolactone, and the liquid formulation provides for aspironolactone exposure that is about 15% greater than a spironolactonedrug exposure obtained when orally administering to a subject a tabletformulation comprising spironolactone.

In a third aspect of the eighth embodiment, the liquid formulationcomprises 100 mg spironolactone and the tablet formulation comprises 100mg spironolactone, and the liquid formulation provides for aspironolactone exposure that is about 37% greater than a spironolactonedrug exposure obtained when orally administering to a subject a tabletformulation comprising spironolactone.

In a fourth aspect of the eighth embodiment, the edema is associatedwith hepatic cirrhosis, congestive heart failure, or nephrotic syndrome.

Liquid formulations described herein unexpectedly provide improvedbioavailability when compared to ALDACTONE® tablets permitting a dosereduction in the amount of administered spironolactone as shown in theninth to twelfth embodiments.

A ninth embodiment is directed to a method for the treatment of heartfailure in a patient, which comprises administering to the patient inneed thereof a liquid formulation comprising 20 mg or 37.5 mgspironolactone once daily or once every other day, wherein said patienthas a serum potassium level of ≤5.0 mEq/L and an estimated glomularfiltration rate (eGFR)>50 mL/min/1.73 m².

In a first aspect of the ninth embodiment, the method comprisesadministering to the patient the liquid formulation comprising 20 mgspironolactone once daily.

In a second aspect of the ninth embodiment, the method comprisesadministering to the patient the liquid formulation comprising 20 mgspironolactone once every other day.

In a third aspect of the ninth embodiment, the method comprisesadministering to the patient the liquid formulation comprising 37.5 mgspironolactone once daily.

As a point of reference, the ALDACTONE® (spironolactone) tabletsprescribing information, as of Oct. 22, 2014, recommends administeringALDACTONE® (spironolactone, 25 mg) tablet once daily for the treatmentof severe heart failure if the patient's serum potassium is ≤5.0 mEq/L.In contrast, the liquid formulation described herein provides for anadministration of 20 mg spironolactone once daily for the treatment ofsevere heart failure if the patient's serum potassium level of ≤5.0mEq/L, which corresponds to a dose reduction of 20%.

A tenth embodiment is directed to a method for the treatment of heartfailure in a patient, which comprises administering to the patient inneed thereof a liquid formulation comprising 10 mg spironolactone oncedaily or once every other day, wherein said patient has a serumpotassium level of ≤5.0 mEq/L and an estimated glomular filtration rate(eGFR) between 30 to 50 mL/min/1.73 m².

An eleventh embodiment is directed to a method for the treatment ofedema associated with hepatic cirrhosis in a patient, which comprisesadministering to the patient in need thereof a liquid formulationcomprising 75 mg to 300 mg spironolactone daily, in a single or adivided dose.

In a first aspect of the eleventh embodiment, the method comprisesadministering to the patient the liquid formulation comprising 75 mg to150 mg spironolactone, in a single or a divided dose.

In a second aspect of the eleventh embodiment, the method comprisesadministering to the patient the liquid formulation comprising 75 mgspironolactone, in a single or a divided dose.

In a third aspect of the eleventh embodiment, the method comprisesadministering to the patient the liquid formulation comprising 150 mgspironolactone, in a single or a divided dose.

A twelfth embodiment is directed to a method for the treatment ofhypertension in a patient, which comprises administering to the patientin need thereof a liquid formulation comprising 20 mg to 75 mgspironolactone daily, in a single or a divided dose.

In a first aspect of the twelfth embodiment, the method comprisesadministering to the patient the liquid formulation comprising 20 mgspironolactone, in a single or a divided dose.

In a second aspect of the twelfth embodiment, the method comprisesadministering to the patient the liquid formulation comprising 75 mgspironolactone, in a single or a divided dose.

In a third aspect of the twelfth embodiment, the hypertension isessential hypertension.

In an aspect of any one of the eighth through twelfth embodiments, theliquid formulation is a ready-to-use liquid formulation, comprising: (a)0.50% w/v of spironolactone; (b) from 0.18% w/v to 0.36% w/v of axanthan gum; (c) optionally a sufficient amount of a buffer to maintainthe pH of the pharmaceutical composition from 4.5 to 5.5; and (d) asufficient amount of a water vehicle, wherein the formulation exhibits aspironolactone content of 100±10% labeled content for about 24-monthswhen stored at 25±2° C. and 40±5% relative humidity.

EXAMPLES

Spironolactone is commercially available as a micronized or unmicronizedsolid. The median (volume) particle size of commercially availableunmicronized spironolactone was 7.47 μm, 18.3 μm, and 35.5 μm for D(v,0.1), D(v, 0.5), and D(v, 0.9), respectively. The manufacturer'sspecifications for the micronized spironolactone is <10 μm (not lessthan 90.0%) and <25 μm (not less than 99.0%). The micronizedspironolactone used in the examples described herein, e.g., Example 2,had a particle size of about 0.42 about 3.64 and about 9.42 for D(v,0.1), D(v, 0.5), and D(v, 0.9), respectively. A dissolution profile forunmicronized spironolactone was slower compared to micronizedspironolactone. For instance, in a dissolution study done in a mannerconsistent with USP <711>, the unmicronized spironolactone at 5-minutesresulted in about 50% of labeled content dissolved, while at the sametime the micronized spironolactone resulted in about 90% of labeledcontent dissolved. Accordingly, in the exemplified embodiments thatfollow, spironolactone refers to micronized spironolactone.

Xanthan gum (i.e., Xanthan Gum, NF) is a water soluble hydrocolloid thatacts as the suspending agent in the composition by increasing theviscosity of the continuous (aqueous) phase which reduces sedimentation.Xanthan gum is commercially available, used as purchased, and complieswith USP-NF requirements.

Simethicone Emulsion is used as an anti-foaming agent in thecompositions described herein. It is a water-dilutable, non-ionicemulsion containing about 30% simethicone, about 1-5% silica gel, about1-5% polyethylene glycol stearate, and water. Simethicone Emulsion iscommercially available, used as purchased, and complies with USP-NFrequirements.

Sorbic acid is an antimicrobial preservative. Sorbic Acid iscommercially available, used as purchased, and complies with USP-NFrequirements.

Potassium Sorbate is an antimicrobial preservative. Potassium Sorbate iscommercially available, used as purchased, and complies with USP-NFrequirements.

Saccharin sodium is a sweetening agent used to improve the palatabilityof the compositions described herein. Saccharin Sodium is commerciallyavailable, used as purchased, and complies with USP-NF requirements.

Citric Acid is a pH modifier (buffering agent) used to maintain thecomposition pH from about 4.5 to about 5.5. Citric Acid is commerciallyavailable, used as purchased, and complies with USP-NF requirements.

Sodium Citrate Dihydrate is a pH modifier (buffering agent) used tomaintain the composition pH of about 4.5 to about 5.5. Sodium CitrateDihydrate is commercially available, used as purchased, and complieswith USP-NF requirements. One of ordinary skill would recognize thatother forms of citrate may be used in the compositions described herein.

Magnasweet 110 (i.e., sweetener) is a sweetening agent used for maskingafter-tastes and enhancing sweetness. Magnasweet 110 contains from 8.5to 10% w/w monoammonium glycyrrhizinate, as measured by the content ofglycyrrhizic acid, in a glycerin vehicle having a specific gravity ofabout 1.27. A typical amount of monoammonium glycyrrhizinate, asmeasured by the content of glycyrrhizic acid, found in Magnasweet 110 isabout 9.9% w/w. Magnasweet 110 is commercially available and used aspurchased.

Glycerin is used as a dispersing agent for the spironolactone. Glycerinis commercially available, used as purchased, and complies with USP-NFrequirements.

Artificial banana flavor (i.e., fruit flavor) is a flavor used toimprove the palatability of the composition. In addition to theflavoring substances, artificial banana flavor contains a vehiclecomprised of propylene glycol (70-80%), water (5-15%), and ethyl alcohol(1-10%). Artificial banana flavor is commercially available and used aspurchased.

Purified water, which meets USP-NF requirements, is used as the primarysolvent for the excipients and diluent for the compositions describedherein.

Specific gravity was measured in a manner consistent with USP <841>,Method I, using a calibrated pycnometer at a temperature of 25° C. beingcareful to exclude foam and air bubbles.

Dosage uniformity was measured in a manner consistent with USP <905>.

Dissolution was measured in a manner consistent with USP <711> reportingthe amount of dissolved spironolactone as a percent of labeled contentwith an associated relative standard devision (“RSD”).

Amounts of spironolactone, related impurities (e.g., canrenone andβ-spironolactone), and sorbate were determined by HPLC.

Resuspendability tests for a given sample stored under long-term andaccelerated conditions. Analysis of samples is performed using a nominalconcentration of about 0.50 mg/ml spironolactone. The followingprocedure was employed for the resuspendability test: (1) Shakepharmaceutical composition (spironolactone concentration of 5.0 mg/mL)composition thoroughly for 5 seconds, 10 seconds and 15 seconds. Invertthe bottle to aid in mixing. (Additional time points may be added ifnecessary). Note: shake times are cumulative. Therefore, after the firstshake of 5 seconds a sample aliquot is withdrawn (5 second sample), thenthe sample is shaken for an additional 5 seconds to obtain a 10 secondaliquot and so on. (2) Transfer approximately 5.0 mL of suspension aftereach shake time, accurately weighed, to a 50-mL volumetric flask. (3)Dilute to volume with Diluent and mix well. (4) Filter a portion of thesample through a filter (Whatman 0.45 μm Nylon with glass microfiber(GMF) or equivalent) discarding at least the first 2 mLs.

Samples were assayed by HPLC using a Waters Sunfire C-18, 10 um, 4.6mm×150 mm column (or its equivalent) operating at a column temperatureof 40° C. (sample Temperature: Ambient) with a mobile phase comprised of50:50% v/v acetonitrile:water operating at a flow rate of 1.0 mL/min andan injection volume of 5 μL. Spironolactone elutes with an approximateretention time of about 7.5 min and the chromatogram peak is detectedusing ultraviolet light at a wavelength of 238 nM (Attenuation: 1 AUFS).A typical chromatogram runs for 10 minutes.

The reported amount of spironolactone (expressed as a % of thespironolactone labeled content) is determined by HPLC by reference to asuitable calibration curve.

Particle size measurements were performed on spironolactone (prior tocomposition manufacture) and on the particulate matter present in thecompositions described herein by laser diffraction. The reportedparticle sizes D(v, 0.1), D(v, 0.5), and D(v, 0.9) relate to the massmedian diameter (in μm) of the volume of distribution of the givenparticles. For instance, D(v, 0.1) (in μm) indicates that 10% of thesample mass is smaller than that value and 90% larger than that value.D(v, 0.5) (in μm) indicates that 50% of the sample mass is smaller thanthat value and 50% of the sample mass is larger than that value.Finally, D(v, 0.9) (in μm) indicates that 90% of the sample mass issmaller than that value and 10% of the sample mass is larger than thatvalue. Alternatively, particle size can be estimated using opticalmicroscopy.

Viscosity measurements were made in a manner consistent with USP <912>with the following instrument parameters: Helipath T-Bar (S91) withdimensions of 1 mm thick and 48 mm across, spindle speed (60 rpm or 573rad/sec), 600 mL test substance container having an inner diameter of 85mm. Results are obtained at 25±1° C. and are presented with units ofcenti-Poise (cP).

pH was measured in a manner consistent with USP <791>. Typically, asample was prepared by shaking a sample container for at least 15seconds with inversion of the container so as to aid sample mixing. Asufficient amount of mixed sample was transferred into a suitable vesselso as to measure the pH.

Anti-microbial effectiveness testing was performed by an independentlaboratory in a manner consistent with USP <51>.

Microbiological examination was performed by an independent laboratoryin a manner consistent with USP <61> and USP <62>.

Unless stated otherwise, the bottles used for the compositions describedherein preferably comprise a polyethylene terephthalate (PETE) resinhaving an amber color. The amber bottles described herein have volumesof 4 oz. (about 118 mL) or 16 oz (about 473 mL) and have an ultravioletlight (290-450 nm) transmission less than about 10%. The bottlescontaining the compositions described herein include caps so as tomaintain an enclosed composition.

Comparative Example 1. Methylcellulose-Containing Composition

A composition similar to U.S. Pat. No. 4,837,211 was prepared. A 40 Lbatch was manufactured and packaged into 16 oz. amber PETE bottles. Thecompositional makeup is summarized in Table 1.

TABLE 1 Compositional Makeup of Comparative Example 1Ingredients/Quality Standards mg % w/v Spironolactone 5.00 0.500Methylcellulose 12.00 1.200 Simethicone Emulsion 2.0 0.20 Sorbic Acid0.50 0.050 Potassium Sorbate 2.00 0.200 Saccharin Sodium 1.35 0.135Sweetener 0.56 0.056 Glycerin 17.64 1.720 Fruit Flavor 2.00 0.200Purified Water QS to 1 mL QS

The amount of simethicone emulsion in Comparative Example 1 is 0.20%w/v, while the amount of simethicone emulsion found in the compositiondescribed in U.S. Pat. No. 4,837,211 is 0.067% w/v.

The spironolactone was dispersed in glycerin and sweetener. Separately,a solution containing methylcellulose (Methocel A4C) in water was cooledto 15° C. for 30 minutes to allow complete hydration of themethylcellulose. The product assayed at 99.2%, 101.5%, and 99.9% forbeginning, middle, and end of the packaging process. Table 2 summarizesthe observed stability data for the composition of Comparative Example 1under accelerated and long-term storage conditions.

TABLE 2 Observed Stability Data for Composition of ComparativeExample 1. Long- Accelerated Term Attribute Initial 1-mo 2-mo 3-mo 3-moPHYSICAL Conforms Conforms Conforms Conforms Conforms INSPECTION pH5.043 5.12 5.12 5.14 5.14 SPECIFIC GRAVITY 1.0093 1.0096 1.0094 1.00971.0096 DISSOLUTION <711>  5 min mean 89 95 97 95 95 % RSD 3.3 0.9 2.40.5 1.8 10 min mean 92 99 103 100 99 % RSD 3.5 0.5 0.4 1.0 0.4 15 minmean 93 100 103 100 100 % RSD 3.8 0.4 0.0 0.5 0.5 30 min mean 93 100 103101 100 % RSD 3.4 0.4 0.5 0.0 0.4 45 min mean 93 101 104 101 100 % RSD3.8 0.5 0.4 0.4 1.3 60 min mean 93 100 105 101 99 % RSD 3.4 0.4 1.2 0.42.9 PARTICLE SIZE^(a) D(v, 0.1) μm 2.38, 2.36 2.18, 2.18 2.14, 2.492.15, 2.13 2.13, 2.19  D(v, 0.5) μm 8.86, 8.83 7.97, 7.94 7.93, 8.908.03, 7.96 7.60, 7.67  D(v, 0.9) μm 25.9, 26.1 27.3, 29.0 26.9, 29.622.3, 22.1 2.1, 20.1 ASSAY (% l.c.) 101.40, 99.34 100.51 90.7 83.4101.21 REL IMPURITIES (%) Canrenone ND 0.04 ND 0.06 0.03 Unidentified NDND ND ND ND Total ND 0.04 ND 0.06 0.03 PRESERVATIVE 102.14 95.33 94.3994.27 94.52 (% Sorbate) VISCOSITY <912> 76.3 45.3 55.0 45.3 46.9 (cP)^(a)Reported particle size is of the solid material in the composition.

ASSAY results at three months for accelerated and long-term storageconditions are suspected to be low due to insufficient shaking of theproduct during sample preparation. It was determined that the methodsample preparation required shaking the sample (inverted) for 60seconds. The low ASSAY values were not confirmed by the 3 monthDISSOLUTION results or the 3 month time point for the ResuspendabilityTests. These aberrant results highlight the importance ofresuspendability of the product.

Resuspendability tests were performed on the product during stability.The purpose of this study was to evaluate the required shake time toprovide a uniform product after accelerated (40° C./≤25% RH) andlong-term (25° C./40% RH) storage conditions. Table 3 summarizes theassayed amounts (% labeled content (“l.c.”)) of spironolactone observedduring the Resuspendability Tests.

TABLE 3 Resuspendability Test Results for Comparative Example 1 underAccelerated and Long-Term Storage Conditions % 1.c. Spironolactone ShakeAccelerated Long-Term Time (sec) Initial 1-mo 2-mo 3-mo 2-mo 3-mo 1584.30 59.47 76.29 74.37 79.15 59.75 30 96.82 77.77 87.09 82.46 94.9275.03 60 101.45 97.91 99.33 93.41 100.91 90.21 120 100.76 100.09 101.41103.25 100.86 102.11

Resuspendability Tests (after long-term storage) show upwards of 60-120seconds of vigorous shaking required to resuspend the spironolactone.This amount of shaking is not a desirable attribute for suspensionsbecause it can lead to poor patient compliance. Further, inadequateresuspension could lead to potentially unwanted dosing errors. Inparticular, the low viscosities observed for the Comparative Example 1composition are believed to result in an increase in sedimentation.Thus, it is clear that a balance between viscosity and sedimentationmust be achieved highlighting the importance of a certain viscosityrange. In view of the excessive shake time required for thiscomposition, efforts were made to identify a suitable suspending agent.

As a part of this effort, seven different compositions containingvarying amounts of suspending agents (methylcellulose, xanthan gum, andmagnesium aluminometasilicate) were prepared and evaluated. Table 4summarizes the compositional makeup of seven different compositions.

TABLE 4 Compositional Makeup of Comparative Examples 2-8 ComparativeExamples 2 3 4 5 6 7 8 Ingredients % w/v % w/v % w/v % w/v % w/v % w/v %w/v Spironolactone 0.500 0.500 0.500 0.500 0.500 0.500 0.500Methylcellulose 1.20 1.20 1.20 — — — — Xanthan Gum 0.25 0.13 — 0.13 0.250.25 0.25 Microcrystalline Cellulose^(a) — — — 2.40 — — — MAS^(d) — —0.500 — — 1.00 0.50 Simethicone Emulsion 0.20 0.20 - 0.20 0.20 - 0.20Sorbic Acid 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Potassium Sorbate 0.200.20 0.20 0.20 0.20 0.20 0.20 Saccharin Sodium 0.135 0.135 0.135 0.1350.135 — 0.135 Sweetener^(b) 0.25 0.50 0.50 0.50 0.50 — 0.50 Glycerin1.764 1.764 1.764 1.764 1.764 15.00 5.00 Fruit Flavor^(c) 0.300 0.3000.300 0.300 0.300 0.30 — Propylene Glycol — — — — — 5.00 5.00 Sucralose— — — — — 0.10 — Citric Acid Anhydrous — — — — — — 0.20 Sodium CitrateDihydrate — — — — — — 0.05 Purified Water QS QS QS QS QS QS QS^(a)Microcrystalline Cellulose (Avicel RC-611) ^(b)MAS (amorphousmagnesium aluminometasilicate, Neusilin ®). ^(c)Sweetener (Magnasweet110) ^(d)Fruit Flavor (Banana Flavor)

In Comparative Example 2, a 1-L batch containing xanthan gum (0.25%) wasadded to the Comparative Example 1 composition. No sedimentation wasnoted after three days, but the product was very viscous and thereforeis not a viable composition. Entrapped air bubbles were also noted inthe suspension after three days which could lead to dosing errors.

In Comparative Example 3, a 1-L batch containing xanthan gum (0.13%) wasadded to the Comparative Example 1 composition. No sedimentation wasnoted after several days. The suspension appeared to be more viscousthan the composition of Comparative Example 1 but acceptable. This is apotentially viable composition.

In Comparative Example 4, a 1-L batch containing amorphous magnesiumaluminometasilicate (Neusilin®) was added to the Comparative Example 1composition. After 24 hours, the sedimentation caked at the bottom anddid not resuspend easily. This is not a viable composition.

In Comparative Example 5, methylcellulose used in the ComparativeExample 1 composition was replaced with xanthan gum (0.13%) andmicrocrystalline cellulose (Avicel RC-611 at 2.4%) for a 1-L batch. Nosedimentation was noted. After 24 hours the suspension became veryviscous and non-pourable. Upon shaking, the suspension exhibitedshear-thinning properties and became pourable. This is not an idealcomposition in terms of practical use.

In Comparative Example 6, methylcellulose used in Comparative Example 1was replaced with xanthan gum (0.25%) for a 1-L batch. The suspensionwas elegant and no sedimentation was noted visually after several days.The product appeared to be easily resuspendable. This is a potentiallyviable composition.

In Comparative Example 7, methylcellulose used in Comparative Example 1was replaced with xanthan gum (0.25%) and further included magnesiumaluminometasilicate (Neusilin®), glycerin, sucralose, propylene glycol,sorbic acid, potassium sorbate, banana flavor, citric acid, sodiumcitrate, and water in the stated amounts for a 1-L batch. There was nosedimentation noted but significant foaming (entrapped air bubbles) wasvisually present after several days. This is not a viable composition.

In Comparative Example 8, methylcellulose used in Comparative Example 1was replaced with xanthan gum (0.25%) and further included magnesiumaluminometasilicate (Neusilin®), glycerin, simethicone, sweetener,sodium saccharin, propylene glycol, sorbic acid, potassium sorbate,sodium citrate, citric acid, banana flavor, and water for a 1-L batch.There was no sedimentation noted after one day. This is a potentiallyviable composition.

In view of the observations gleaned from the compositions described inComparative Examples 2-8, xanthan gum at approximately 0.25% appeared tobe a suspending agent that provided an elegant easily resuspendablesuspension. An added advantage realized by xanthan gum comes fromprocess considerations. For instance, methylcellulose should besufficiently hydrated prior to use, which requires heating and coolingan aqueous composition containing methycellulose. There is no such addedrequirement for xanthan gum. Further development work focuses on theaddition of xanthan gum and removal of methylcellulose.

Example 1. Composition that Replaces Methylcellulose with Xanthan Gum

Based on previously mentioned development work, xanthan gum was selectedas a potential suspending agent instead of methylcellulose. Table 5summarizes the compositional makeup of the Example 1 composition.

TABLE 5 Compositional Makeup of Example 1 CompositionIngredients/Quality Standards mg % w/v g/Batch Spironolactone 5.0000.5000 50.00 Xanthan Gum 2.500 0.2500 25.00 Simethicone Emulsion 2.0000.2000 20.00 Sorbic Acid 0.5000 0.05000 5.000 Potassium Sorbate 2.0000.2000 20.00 Saccharin Sodium 1.350 0.1350 13.50 Sweetener 5.000 0.500050.00 Glycerin 17.64 1.764 176.4 Fruit Flavor 3.000 0.3000 30.00Purified Water, USP QS to 1 mL QS QS to 10 L

A 10 L batch was manufactured as follows. Xanthan gum and 7.0 kg ofpurified water were mixed at 1000 rpm in a first container for 15minutes. Simethicone emulsion was added to the first containercontaining xanthan gum, and after addition, the composition was mixed at1000 rpm for 5 minutes. Next, sorbic acid, potassium sorbate, and sodiumsaccharin were added to said first container followed by mixing at 900rpm for 10 minutes. In a separate container, sweetener, glycerin, and125 g of purified water were mixed at 900 rpm for 1 minute. To saidsecond container, spironolactone was dispersed by mixing at 550 rpm for5 minutes. The contents of the second container were then transferred tothe first container, which was followed by the addition of fruit flavor.The contents of the first container after fruit flavor addition weremixed at 950 rpm for 2 minutes. Finally, the remaining amount ofpurified water was added to the first container and said contents weremixed at 950 rpm for 15 minutes. The contents of the first containerwere then packaged into 4 oz. amber PETE bottles. Again, due to theremoval of methylcellulose (Methocel A4C), the process is simplifiedsince heating and cooling is not required for xanthan gum.

Table 6 summarizes the observed stability data for the Example 1composition under accelerated and long-term storage.

TABLE 6 Observed Stability Data for Example 1 under Accelerated andLong-Term Storage Conditions. Accelerated Long-Term Attribute Initial1-mo 2-mo 3-mo 3-mo PHYSICAL INSPECTION Conforms Conforms ConformsConforms Conforms pH 5.044 5.046 5.037 5.005 5.092 SPECIFIC GRAVITY1.008 1.008 1.007 1.008 1.008 DISSOLUTION <711>  5 min mean 89 90 91 9392 % RSD 3.6 0.7 0.9 0.4 0.0 10 min mean 96 97 98 99 98 % RSD 2.6 0.50.6 0.0 0.4 15 min mean 97 98 99 101 100 % RSD 2.6 0.4 0.5 0.0 0.6 30min mean 98 100 99 101 100 % RSD 2.5 0.0 0.4 0.4 0.0 45 min mean 98 99100 102 100 % RSD 2.6 0.4 0.6 0.4 0.0 60 min mean 98 99 99 101 100 % RSD3.0 0.6 0.5 0.5 0.0 PARTICLE SIZE^(a) D(v, 0.1) μm 2.48, 2.47 2.21, 2.142.72, 2.58 2.65, 2.64 2.72, 2.73 D(v, 0.5) μm 9.41, 9.47 8.84, 8.489.43, 9.11 9.33, 9.11 9.63, 9.64 D(v, 0.9) μm 20.8, 20.9 19.8, 19.220.6, 20.2 20.2, 19.7 20.9, 20.9 ASSAY (% l.c.) 99.0 99.5 101.4 103.0101.2 REL IMPURITIES (%) Canrenone 0.08 0.07 0.10 0.3 <0.10β-Spironolactone 0.10 0.09 0.09 NR^(b) NR^(b) Unidentified 0.09 0.06 NDND ND Total 0.27 0.22 0.19 0.3 <0.10 PRESERVATIVE 96.64 92.05 90.58 90.091.5 (% Sorbate) VISCOSITY <912> 145.0 136.5 129.7 129.3^(c) 145.6 (cP)NR (not reported), ND (not determined) ^(a)Reported particle size is ofthe solid material in the composition. ^(b)β-spironolactone is a processimpurity and not reported after 3 months. ^(c)After 6-months long-termstorage, the observed viscosity is 102.5 cP.

The observed viscosity during the reported time intervals was found tobe at least 129 cP. As described elsewhere, the composition should havea viscosity that ranges from 100 cP to 300 cP. Not to be bound bytheory, it is believed that a viscosity less than 100 cP promotessedimentation, which may be problematic with respect to theresuspendability of the pharmaceutical composition. A viscosity greaterthan 300 cP results in a solution that is too viscous, which may beproblematic with respect to product dispensation, i.e., the solution maybecome too thick to dispense easily.

Resuspendability tests were performed on the Example 1 composition. Thepurpose of this study was to evaluate the required shake times toprovide a uniform product after accelerated and long-term storageconditions. Table 7 summarizes the results of the resuspendabilitytests.

TABLE 7 Resuspendability Tests (% l.c. spironolactone) for Example 1Composition under Accelerated and Long-Term Storage Conditions % l.c.Spironolactone Shake Accelerated Time (sec) Initial 1-mo 2-mo 3-mo 6-mo5 — — 100.8 100.9 97.1 10 — — 101.2 100.9 103.6 15 99.0 99.2 — 101.6103.9 30 99.2 99.6 102.4 — — 60 98.7 99.0 — — — Long-Term Shake ThreeSix Nine Twelve Time (sec) Initial Months Months Months Months 5 — 100.9100.6 100.7 91.4 10 — 100.9 101.7 105.9 102.3 15 99.0 101.6 101.7 106.3102.7 30 99.2 — — — — 60 98.7 — — — —

The stability of the Example 1 composition with xanthan gum (instead ofmethylcellulose) is acceptable after 3 months accelerated storage. Afterlong-term storage, the product resuspends after only 5 seconds ofshaking compared to 60-120 seconds for the composition of ComparativeExample 1 (with methylcellulose). The particle size of the compositiondoes not change on stability.

Example 2: Alternate Composition with Xanthan Gum and Citrate Buffer

An alternative composition was manufactured like Example 1, with theexception that a citrate buffer was added. Table 8 summarizes thecompositional makeup of the Example 2 composition.

TABLE 8 Compositional Makeup of Example 2 CompositionIngredients/Quality Standards mg % w/v Spironolactone Micronized 5.0000.5000 Xanthan Gum 2.500 0.2500 Simethicone Emulsion 2.000 0.2000 SorbicAcid 0.5000 0.05000 Potassium Sorbate 2.000 0.2000 Saccharin Sodium1.350 0.1350 Sweetener 4.000 0.4000 Glycerin, USP 17.64 1.764 FruitFlavor 3.000 0.3000 Citric Acid Anhydrous 2.388 0.2388 Sodium CitrateDihydrate 3.696 0.3696 Purified Water, USP QS to 1 mL QS

A 12 L batch was manufactured as follows. Xanthan gum and 8.0 kg ofpurified water were mixed at 900 rpm in a first container for 30minutes. Simethicone emulsion was added to the first containercontaining xanthan gum, and after addition, the composition was mixed at950 rpm for 5 minutes. Next, sorbic acid, potassium sorbate, and sodiumsaccharin were added to said first container followed by mixing at 950rpm for 10 minutes. Citric acid and sodium citrate were then added tothe first container and the contents were mixed at 1000 rpm for 10minutes. In a separate container, sweetener, glycerin, and 125 g ofpurified water were mixed at 400 rpm for 1 minute. To said secondcontainer, spironolactone was dispersed by mixing at 1050 rpm for 5minutes. The contents of the second container were then transferred tothe first container, which was followed by the addition of fruit flavor.The contents of the first container after fruit flavor addition weremixed at 1250 rpm for 2 minutes. The remaining amount of purified water(q.s. to 95% of batch) was added to the first container and saidcontents were mixed at 750 rpm for 5 minutes. An optional step requireschecking and adjusting the pH by adding the appropriate amounts of 10%(w/w) citric acid solution or 10% (w/w) sodium citrate solution. Thecontents of the first container were then packaged into 4 oz. amber PETEbottles.

Observed stability data for the Example 2 composition under acceleratedand long-term storage are reported in Tables 9-10, respectively.

TABLE 9 Observed Stability Data for Example 2 under Accelerated StorageConditions. Accelerated Attribute Initial 1 month 2 months 3 months 6month PHYSICAL INSPECTION Conforms Conforms Conforms Conforms ConformsPH 5.032 5.037 5.059 5.022 5.005 SPECIFIC GRAVITY 1.012 1.013 1.0101.013 1.013 DISSOLUTION <711>  5 min mean 91 93 91 93 95 % RSD 1.3 0.90.8 0.4 0.0 10 min mean 98 99 97 99 101 % RSD 0.5 0.5 0.4 0.4 0.0 15 minmean 99 100 98 100 103 % RSD 0.4 0.5 0.4 0.8 0.5 30 min mean 100 100 98101 103 % RSD 0.5 0.4 0.5 0.0 0.0 45 min mean 99 101 99 101 103 % RSD0.5 0.5 0.0 0.4 0.5 60 min mean 99 100 99 101 103 % RSD 0.4 0.5 0.0 0.00.0 PARTICLE SIZE^(a) D(v, 0.1) μm 2.24, 2.20 2.02, 2.03 2.39, 2.312.38, 2.41 2.34, 2.07 D(v, 0.5) μm 8.50, 8.54 8.09, 8.18 8.55, 8.468.53, 8.54 8.56, 8.32 D(v, 0.9) μm 18.9, 19.0 18.2, 18.3 18.7, 18.718.7, 18.6 18.7, 18.5 ASSAY (% l.c.) 99.4 100.4 101.0 101.4 103.8 RELIMPURITIES (%) Canrenone 0.07 0.09 0.12 0.4 0.6 β-spironolactone 0.100.09 0.09 NR^(a) NR^(b) Unidentified ND 0.02 0.21 0.4 ND Total 0.17 0.200.21 0.40 0.6 PRESERVATIVE 98.40 95.20 98.98 92.5 89.2 (% Sorbate)VISCOSITY <912> 153.7 155.0 153.1 153.1 139.0 (cP) NR (not reported), ND(not determined) ^(a)Reported particle size is of the solid material inthe composition. ^(b)β-spironolactone is a process impurity and notreported after 3 months.

TABLE 10 Observed Stability Data for Example 2 under Long-Term StorageConditions. Long-Term Attribute Initial 3 months 6 months 9 months 12months PHYSICAL INSPECTION Conforms Conforms Conforms Conforms ConformspH 5.032 5.052 4.988 4.961 5.000 SPECIFIC GRAVITY 1.012 1.013 1.0131.011 1.013 DISSOLUTION <711>  5 min mean 91 93 94 93 93 % RSD 1.3 0.40.4 0.4 0.6 10 min mean 98 99 100 99 100 % RSD 0.5 0.4 0.0 0.4 1.4 15min mean 99 100 101 100 101 % RSD 0.4 0.4 0.0 0.4 0.0 30 min mean 100101 101 101 102 % RSD 0.5 0.4 0.0 0.0 0.5 45 min mean 99 101 101 101 102% RSD 0.5 0.4 0.0 0.4 0.0 60 min mean 99 101 101 101 102 % RSD 0.4 0.40.4 0.0 0.5 PARTICLE SIZE^(a) D(v, 0.1) μm 2.24, 2.20 2.31, 2.36 2.39,2.36 2.17, 2.24 2.17, 2.20 D(v, 0.5) μm 8.50, 8.54 8.49, 8.54 8.61, 8.577.96, 8.08 8.05, 8.14 D(v, 0.9) μm 18.9, 19.0 18.7, 18.7 18.8, 18.717.5, 17.5 17.6, 16.8 ASSAY (% l.c.) 99.4 101.6 102.3 103.3 102.9 RELIMPURITIES (%) Canrenone 0.07 0.09 0.12 0.4 0.1 β-spironolactone 0.100.09 0.09 NR^(b) NR^(b) Unidentified ND 0.02 0.21 0.4 0.1 Total 0.170.20 0.21 0.40 0.1 PRESERVATIVE 98.40 95.20 98.98 92.5 96.7 (% Sorbate)VISCOSITY <912> 153.7 162.5 152.2 161.5 164.1 (cP) NR (not reported), ND(not determined) ^(a)Reported particle size is of the solid material inthe composition. ^(b)β-spironolactone is a process impurity and notreported after 3 months.

The observed viscosity during the reported time intervals was found tobe at least 139 cP. As stated above, the composition should have aviscosity that ranges from 100 cP to 300 cP.

As stated above, Pramar et al., Journal of Clinical Pharmacy andTherapeutics (1992): 17(4): 245-248 report stabilities studies of aspironolactone-containing liquid dosage form containing phosphate (0.05,pH=4.5±0.1) and citrate buffer (0.05 M, pH=4.5±0.1). After 93-days ofstorage at 40° C., Pramar et al. found that the amount of spironolactoneremaining in the phosphate-buffered dosage form to be 91.23±0.51%, whilethe citrate-buffered dosage form to be 80.97±0.84%. In view of thefindings reported by Pramar et al., it was surprising that the additionof citrate buffer resulted in a composition that had an acceptableimpurity profile after accelerated and long-term storage.

Resuspendability tests were performed on the Example 2 composition. Thepurpose of this study was to evaluate the required shake times toprovide a uniform product after accelerated and long-term storageconditions. Table 11 summarizes the results of the resuspendabilitytests.

TABLE 11 Resuspendability Tests (% l.c. spironolactone) for Example 2Composition under Accelerated and Long-Term Storage Conditions % 1.c.Spironolactone Accelerated Shake Time (sec) Initial 1-mo 2-mo 3-mo 6-mo5 — — 102.6 99.0 98.8 10 — — 102.6 101.1 103.0 15 98.5 98.9 100.9 98.9102.7 30 98.4 98.9 — — — 60 98.4 98.6 — — — Long-Term Shake Time (sec)Initial 3-mo 6-mo 9-mo 12-mo 5 — 104.4 101.8 100.9 97.3 10 — 101.5 101.6101.3 102.2 15 98.5 103.5 101.6 101.1 102.8 30 98.4 — — — — 60 98.4 — —— —

The results presented in Table 11 show that the Example 2 compositionresuspends within 5 seconds after shaking under accelerated andlong-term storage.

As a point of reference, FIG. 1 shows the initially observedspironolactone content (% l.c.) as a function of shake-time (in seconds)for the compositions of Example 2 (grey bars) and Comparative Example 1(black bars). FIG. 2 shows the observed spironolactone content (% l.c.)as a function of shake-time (in seconds) for the compositions of Example2 (grey bars) and Comparative Example 1 (black bars) after long-termstorage for 3-months. The data depicted in FIG. 2 shows that thecomposition of Example 2 remains suspended with uniform content evenafter long-term storage for 3-months. This should be contrasted to thecomposition of Comparative Example 1 in which uniform suspensionrequires a shake-time of at least 120 seconds.

The composition of Example 2 was assayed for spironolactone aftershaking well and after allowing the bottle to remain undisturbed for 30minutes, 2 hours, and 4 hours to evaluate the uniformity of thespironolactone under actual conditions of use. The spironolactoneremains suspended and uniform for at least 4 hours after initialshaking. No sedimentation is visually observed even after seven days.Table 12 summarizes the suspension maintenance test for the Example 2composition after initial shaking.

TABLE 12 Suspension Maintenance Tests for Example 2 Composition afterInitial Shaking Time point % l.c. Spironolactone Initial 101.2 30minutes 101.1 2 hours 101.1 4 hours 101.0

The stability of the Example 2 composition with xanthan gum and citratebuffer is acceptable after 3 months accelerated conditions. After longterm storage the product resuspends after only 5 seconds of shakingcompared to 60-120 seconds in the composition described in ComparativeExample 1. The product remains suspended and uniform for at least fourhours after shaking well. Improvements in the resuspendability of theproduct are achieved with this composition.

Use of amber PETE bottles, instead of white HDPE bottles, reduced therate of loss for sorbate. A composition similar to Comparative Example 1(except that glycerin and fruit flavor were present at 1.717 and 0.10%w/v, respectively), was stored in two separate bottles: amber PETE andwhite HDPE. The amount of sorbate (%) in the composition stored in thePETE bottle after long-term storage at 9-months was about 90.7%. Theamount of sorbate (%) in the composition stored in the HDPE bottle afterlong-term storage at 6-months was about 56.7%. In view of these results,a decision was made to use amber PETE bottles due to the extensivesorbate loss in the HDPE bottles. As a point of reference, FIG. 3 showsthe effect of storage on sorbate levels in amber PETE bottles (greybars, Example 2 Composition) and white HDPE bottles (black bars,above-mentioned composition similar to Comparative Example 1).Acceptable sorbate levels are observed in the amber PETE bottles aftersix months accelerated storage. This should be contrasted to thecomposition contained in the white HDPE bottles.

The importance of preservative level is apparent from a preservativeeffectiveness study. In that study, compositions identical to theExample 2 composition were prepared (except for varying levels of totalsorbate (approximately 25%, 50%, and 75%), where total sorbate is theamount of sorbic acid and potassium sorbate). AntimicrobialEffectiveness Testing showed that at a total sorbate level of about 25%,the composition passed against E. coli, P. aeruginosa, S. aureus, and A.brasiliensis, but failed against B. cepacia and C. albicans.Antimicrobial Effectiveness Testing showed that at total sorbate levelsof 50%, the composition passed against E. coli, P. aeruginosa, S.aureus, and A. brasiliensis, and C. albicans, but failed against B.cepacia. Finally, Antimicrobial Effectiveness Testing showed that attotal sorbate levels of 75%, the composition passed against E. coli, P.aeruginosa, S. aureus, and A. brasiliensis, C. albicans, and B. cepacia.And, 100% sorbate levels the composition passed against all of theabove-mentioned organisms.

The stability of the Example 2 composition with xanthan gum (instead ofmethylcellulose) is acceptable after 6 months accelerated storageconditions and 12 months long term storage conditions. After long termstorage, the product resuspends to a suitable level after only 5 secondsof shaking compared to 60-120 seconds observed for the composition ofComparative Example 1 (with methylcellulose). After nine months oflong-term storage visual sedimentation is seen at the bottom of thebottle for the composition of Example 1 that is not noted in thebuffered system (Example 2). This observation is confirmed by long-termstorage resuspendability tests at 9-months (with no shaking) for theExample 1 composition (16.4% l.c.) and the Example 2 composition (89.1%l.c.) This is a surprising discovery that after long-term storage theExample 2 composition exhibits a much higher level of uniformity withoutshaking, which suggests that the citrate buffer is serving to retard thesedimentation rate. Improvements in the resuspendability of the productare seen even in the 4 oz. PETE bottle. The particle size of the Example2 composition does not change on stability. Improvements andsimplification in the process are also gained by replacing themethylcellulose with xanthan gum.

Another point of interest stems from the observed viscosity values forthe Example 1 and Example 2 compositions under accelerated storageconditions. For instance, the Example 1 composition (without citratebuffer) after 6-months at accelerated storage had an observed viscosityof 102.5 cP. This should be contrasted to the Example 2 composition(with citrate buffer) after 6-months at accelerated storage where theobserved viscosity was 139.0 cP. This amounts to a change in viscosityof about 36%. This was an unexpectedly surprising finding, whichprovided the motivation to pursue further a composition that contains acitrate buffer.

It is also of interest to compare the viscosity values for thecompositions of Comparative Example 1, Example 1, and Example 2, after3-months of storage under accelerated conditions. For example, theobserved viscosity value for the Comparative Example 1 composition was45.3 cP, after 3-months storage under accelerated conditions. At thesame time point and the same conditions, the observed viscosity valuesfor the Example 1 and Example 2 compositions were 129.3 cP and 153.1 cP,respectively. This information shows the unexpected superiority ofxanthan gum with respect to methylcellulose.

Examples 3-4. Spironolactone Compositions Containing Different Amountsof Xanthan Gum

Two different compositions with different amounts of xanthan gum wereprepared and different viscosities. The compositional makeup of Example3 and Example 4 is summarized in Table 13.

TABLE 13 Compositional Makeup of Examples 3-4 Example 3 Example 4Ingredients/Quality Standards mg % w/v mg % w/v SpironolactoneMicronized 5.000 0.5000 5.000 0.5000 Xanthan Gum 1.800 0.1800 3.6000.3600 Simethicone Emulsion 2.000 0.2000 2.000 0.2000 Sorbic Acid 0.50000.05000 0.5000 0.05000 Potassium Sorbate 2.000 0.2000 2.000 0.2000Saccharin Sodium 1.350 0.1350 1.350 0.1350 Sweetener 4.000 0.4000 4.0000.4000 Glycerin, USP 17.64 1.764 17.64 1.764 Fruit Flavor 3.000 0.30003.000 0.3000 Citric Acid Anhydrous 2.010 0.201 2.010 0.201 SodiumCitrate Dihydrate 4.280 0.4280 4.280 0.4280 Purified Water, USP QS to 1mL QS QS to 1 mL QS Viscosity (cP) 108.0 299.4 pH 4.8 4.9

The compositions of Examples 3-4 were assayed for spironolactone aftershaking well and after allowing the bottle to remain undisturbed for 30minutes, 2 hours, and 4 hours to evaluate the uniformity of thespironolactone under actual conditions of use. The spironolactoneremains suspended and uniform for at least 4 hours after initialshaking. No sedimentation is visually observed even after seven days.The results are found in Table 14.

TABLE 14 Suspension Maintenance Tests for Example 3-4 Compositions afterInitial Shaking % l.c. Spironolactone Time point Example 3 Example 4Initial 102.4 101.5 30 minutes 102.1 101.2 2 hours 101.2 101.1 4 hours102.1 101.0

In view of these results, a viscosity range of 100 to 300 cP was foundto be acceptable.

Example 5. Composition Containing Xanthan Gum and Citrate Buffer

An alternative composition was manufactured like Example 2 except at alarger (250 L) scale. Table 15 summarizes the compositional makeup ofthe Example 5 composition.

TABLE 15 Compositional Makeup of Example 5 Ingredients mg % w/vSpironolactone 5.000 0.5000 Xanthan Gum 2.500 0.2500 SimethiconeEmulsion 2.000 0.2000 Sorbic Acid 0.5000 0.05000 Potassium Sorbate 2.0000.2000 Saccharin Sodium 1.350 0.1350 Sweetener^(a) 4.000 0.4000 Glycerin17.64 1.764 Fruit Flavor^(b) 3.000 0.3000 Citric Acid Anhydrous 1.7580.1758 Sodium Citrate Dihydrate 4.660 0.4660 Purified Water QS to 1 mLQS pH 4.5-5.5^(c, d) ^(a)Sweetener (Magnasweet 110) ^(b)Fruit Flavor(Banana Flavor). ^(c)pH adjustment with 10% (w/w) Citric Acid Solutionor 10% (w/w) Sodium Citrate Solution, if necessary. ^(d)The in processpH specification for manufacture was pH of 4.8 to 5.2, but with storagethe pH specification is 4.5 to 5.5.

Three separate batches (250 L each) were prepared in a manner comparableto that described for the Example 2 composition. The average viscosityof the three batches was determined to be 155±2 cP, while the averagespecific gravity was determined to be 1.012±0.001. The measured bulk pHwas 5.0 for each batch.

Each batch was packaged in amber PETE containers (4 oz. (118 mL fillvolume) and 16 oz. (473 mL fill volume)). The stability of the Example 5Composition with xanthan gum is acceptable after accelerated (6-months)and long-term (12-months) storage. Particle size and viscosity valueswere consistent to those values reported for the Example 2 compositionfor accelerated and long-term storage. Resuspendability tests show thatthe Example 5 composition resuspends within 5-15 seconds afteraccelerated and long-term storage. The results for a portion of thepackaged batch (4 oz.) is summarized in Table 16.

TABLE 16 Resuspendability Tests (% l.c. spironolactone) for Example 5Composition under Accelerated and Long-Term Storage Conditions % l.c.Spironolactone Accelerated Shake Time (sec) Initial 1-mo 2-mo 3-mo 6-mo5 100.5 101.1 102.0 102.9 101.9 10 100.4 101.7 101.7 103.3 103.0 15100.5 101.5 102.3 103.4 103.9 Long-Term Shake Time (sec) Initial 3-mo6-mo 9-mo 12-mo 5 100.5 101.2 100.8 99.5 104.0 10 100.4 102.3 102.6102.5 104.1 15 100.5 102.2 101.0 102.6 103.6

The data found in Table 16 shows that the Example 5 composition exhibitssatisfactory resuspendability even after 12-months of long-term storage.The slight, but acceptable, increase in % l.c. spironolactone isbelieved to be due to evaporative loss. For instance, after 3-monthslong-term storage a weight loss of about 0.4% was observed, while after12-months long-term storage a weight loss of about 1.6% was observed. Aweight loss of not more than 5% at accelerated conditions is consideredto be acceptable.

Example 6: Composition with Xanthan Gum and Citrate Buffer

A composition is manufactured like Example 5 except at a larger (2000 L)scale. Table 17 summarizes the compositional makeup of the Example 6composition.

TABLE 17 Compositional Makeup of Example 6 Ingredients mg % w/v %w/w^(a) Spironolactone 5.000 0.5000 0.4941 Xanthan Gum 2.500 0.25000.2470 Simethicone Emulsion 2.000 0.2000 0.1976 Sorbic Acid 0.50000.05000 0.04941 Potassium Sorbate 2.000 0.2000 0.1976 Saccharin Sodium1.350 0.1350 0.1334 Sweetener^(b) 4.000 0.4000 0.3953 Glycerin 17.641.764 1.743 Fruit Flavor^(c) 3.000 0.3000 0.2964 Citric Acid Anhydrous2.010 0.2010 0.1986 Sodium Citrate Dihydrate 4.280 0.4280 0.4229Purified Water QS to 1 mL QS QS pH 4.5-5.5^(d, e) ^(a)Calculated using aspecific gravity of 1.012. ^(b)Sweetener (Magnasweet 110). ^(c)FruitFlavor (Banana Flavor). ^(d)pH adjustment with 10% (w/w) Citric AcidSolution or 10% (w/w) Sodium Citrate Solution, if necessary ^(e)The inprocess pH specification for manufacture was pH of 4.8 to 5.0, but withstorage the pH specification is 4.5 to 5.5.

Example 7: Pharmacokinetic Comparative Studies

An open label, randomized, two treatment, two period, two sequence,crossover, single dose, oral pharmacokinetic and comparativebioavailability study of: (i) a liquid formulation described herein(see, e.g., Example 5; see also Example 6) comprising spironolactone(dosed at 25 mg or 100 mg) and (ii) ALDACTONE® spironolactone tablets(25 mg or 100 mg) of G.D. Searle LLC, Division of Pfizer Inc. USA, inhealthy, human subjects (N=13 (25 mg) or N=56 (100 mg)) under fastingcondition. Plasma concentrations of spironolactone were measured afteradministration and least squares means for selected pharmacokinetic (PK)parameters were calculated, including the maximum plasma concentration(C_(max)), as well as area under the curve values (i.e., AUC_(0-t) andAUC_(0-∞)). Table 18 provides the least squares geometric means of theselected PK parameters, as well as the calculated ratios and the 90%confidence intervals.

TABLE 18 Pharmacokinetic (PK) Parameters PK Parameter Liquid TabletRatio, % 90% C.I. 25 mg^(a) AUC_(0-t), ng · hr/mL 76.695 67.289 113.978103.02-126.11 AUC_(0-∞), ng · hr/mL 81.556 70.786 115.214 104.19-127.41C_(max), ng/mL 47.360 38.901 121.744 101.43-146.13 100 mg^(b) AUC_(0-t),ng · hr/mL 290.114 211.220 137.352 123.83-152.35 AUC_(0-∞), ng · hr/mL299.509 218.630 136.994 122.45-153.26 C_(max), ng/mL 127.021 76.10165.587 150.42-182.28 ^(a)N = 13, ^(b)N = 56.

From these results it can be seen that the liquid formulation exhibitshigher C_(max)- and AUC-values. Based on the AUC_(0-∞)-values, it can beseen that the liquid formulation provides a greater drug exposure whencompared to the ALDACTONE® tablet formulation dosed at an equivalentamount. For instance, the liquid and tablet provided an AUC_(0-∞) ratioof 115.214 for the 25-mg dose and 137.352 for the 100 mg dose.Therefore, for an equivalent dosage amount the liquid formulationresults in an increase in spironolactone exposure of about 15 to about37% spironolactone when compared to ALDACTONE® tablets. This finding isunexpected and permits a lower dosage amount of the liquidspironolactone formulation when compared to ALDACTONE® tablets.

Alternative embodiments, examples, and modifications which would stillbe encompassed by the disclosure may be made by those skilled in theart, particularly in light of the foregoing teachings. Further, itshould be understood that the terminology used to describe thedisclosure is intended to be in the nature of words of descriptionrather than of limitation.

The subject matter of U.S. patent application Ser. No. 15/665,014, filedon Jul. 31, 2017, U.S. patent application Ser. No. 15/337,559, filed onOct. 28, 2016, and U.S. Provisional Patent Application No. 62/495,583,filed on Oct. 30, 2015, is incorporated by reference in its entirety.Additionally, the references described herein are incorporated byreference in their entirety to the extent necessary. In the event thatthere is a difference in meaning between the incorporated terms and theterms disclosed herein, the meaning of the terms disclosed herein willcontrol.

Those skilled in the art will also appreciate that various adaptationsand modifications of the preferred and alternative embodiments describedabove can be configured without departing from the scope and spirit ofthe disclosure. Therefore, it is to be understood that, within the scopeof the appended claims, the disclosure may be practiced other than asspecifically described herein.

We claim:
 1. A ready-to-use liquid formulation, comprising: micronizedspironolactone in an amount of about 5 mg/mL; xanthan gum in an amountto provide a formulation viscosity of from 100 cP to 300 cP, glycerin inan amount of from 18 mg/mL to 24 mg/mL; a sufficient amount of a citratebuffer to maintain a pH of the formulation from 4.5 to 5.5 and a watervehicle.
 2. The ready-to-use liquid formulation of claim 1, wherein themicronized spironolactone has a median volume particle size of not morethan about 9.6 μm.
 3. The ready-to-use liquid formulation of claim 1,wherein the micronized spironolactone has a median volume particle sizeof about 3.6 μm to about 9.6 μm.
 4. The ready-to-use liquid formulationof claim 1, wherein the xanthan gum is present in an amount of from 1.3mg/mL to 3.6 mg/mL.
 5. The ready-to-use liquid formulation of claim 1,wherein the xanthan gum is present in an amount of from 1.8 mg/mL to 3.6mg/mL.
 6. The ready-to-use liquid formulation of claim 1, wherein theglycerin is present in an amount of from 18 mg/mL to 22 mg/mL.
 7. Theready-to-use liquid formulation of claim 1, wherein the citrate bufferis present in an amount of from about 10 mM to about 100 mM.
 8. Theready-to-use liquid formulation of claim 1, wherein the citrate bufferis present in an amount of from about 10 mM to about 100 mM and whereinthe pH of the formulation ranges from 4.8 to 5.2.
 9. The ready-to-useliquid formulation of claim 1, wherein the citrate buffer comprises from1.7 mg/mL to 2.4 mg/mL citric acid and from 3.6 mg/mL to 4.8 mg/mLsodium citrate.
 10. The ready-to-use liquid formulation of claim 1,wherein the formulation viscosity ranges from 130 cP to 170 cP.
 11. Theready-to-use liquid formulation of claim 1, wherein the spironolactonecontent is 100±10% of labeled content when stored under 25±° C. and 40%relative humidity for 12-months.
 12. A ready-to-use liquid formulation,comprising: micronized spironolactone in an amount of about 5 mg/mL;xanthan gum in an amount to provide a formulation viscosity of from 100cP to 300 cP, a dispersing agent consisting of glycerin in an amount offrom 18 mg/mL to 24 mg/mL; a sufficient amount of a citrate buffer tomaintain a pH of the formulation from 4.5 to 5.5 and a water vehicle.13. The ready-to-use liquid formulation of claim 12, wherein themicronized spironolactone has a median volume particle size of not morethan about 9.6 μm.
 14. The ready-to-use liquid formulation of claim 12,wherein the micronized spironolactone has a median volume particle sizeof about 3.6 μm to about 9.6 μm.
 15. The ready-to-use liquid formulationof claim 12, wherein the xanthan gum is present in an amount of from 1.3mg/mL to 3.6 mg/mL.
 16. The ready-to-use liquid formulation of claim 12,wherein the xanthan gum is present in an amount of from 1.8 mg/mL to 3.6mg/mL.
 17. The ready-to-use liquid formulation of claim 12, wherein theglycerin is present in an amount of from 18 mg/mL to 22 mg/mL.
 18. Theready-to-use liquid formulation of claim 12, wherein the citrate bufferis present in an amount of from about 10 mM to about 100 mM.
 19. Theready-to-use liquid formulation of claim 12, wherein citrate buffer ispresent in an amount of from about 10 mM to about 100 mM and wherein thepH of the formulation ranges from 4.8 to 5.2.
 20. The ready-to-useliquid formulation of claim 12, wherein the citrate buffer comprisesfrom 1.7 mg/mL to 2.4 mg/mL citric acid and/or from 3.6 mg/mL to 4.8mg/mL sodium citrate.
 21. The ready-to-use liquid formulation of claim12, wherein the formulation viscosity ranges from 130 cP to 170 cP. 22.The ready-to-use liquid formulation of claim 12, wherein thespironolactone content is 100±10% of labeled content when stored under25±° C. and 40% relative humidity for 12-months.
 23. The ready-to-useliquid formulation of claim 1, wherein the formulation viscosity rangesfrom 120 cP to 170 cP.
 24. The ready-to-use liquid formulation of claim1, wherein the formulation viscosity ranges from 150 cP to 170 cP. 25.The ready-to-use liquid formulation of claim 1, wherein the xanthan gumis from 1.3 mg/mL to 3.0 mg/mL.
 26. The ready-to-use liquid formulationof claim 1, wherein the micronized spironolactone has a median volumeparticle size of about 3.6 μm.
 27. The ready-to-use liquid formulationof claim 12, wherein the formulation viscosity ranges from 120 cP to 170cP.
 28. The ready-to-use liquid formulation of claim 12, wherein theformulation viscosity ranges from 150 cP to 170 cP.
 29. The ready-to-useliquid formulation of claim 12, wherein the xanthan gum is from 1.3mg/mL to 3.0 mg/mL.
 30. The ready-to-use liquid formulation of claim 12,wherein the micronized spironolactone has a median volume particle sizeof about 3.6 μm.